Transcriptome and Network Dissection of Microsatellite Stable and Highly Instable Colorectal Cancer

Document Type: Systematic Review and Meta-analysis

Authors

1 Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC Canada.

2 Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

3 Department of Cellular-Molecular Biology, Faculty of Biological Sciences and Technologies Shahid Beheshti University of Medical Sciences, Tehran, Iran.

4 Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Abstract

Background: Colorectal cancer (CRC) is one of the most common cancers worldwide with high number of mortality
every year. Microsatellite instability (MSI) is a considerable feature of CRC which affects prognosis and treatment.
High level of MSI or MSI-high (MSI-H) colorectal cancer has better prognosis and immunotherapy response, while
microsatellite stable (MSS) CRC has better response to 5-fluorouracil (5-FU)-based chemotherapy. More studies are
needed, specifically on MSS CRC which has worse prognosis, to further reveal biological differences and similarities
between MSS and MSI colorectal cancer, which may equip us with the knowledge to develop more promising therapeutic
approaches to target both types or be more effective for each type. Methods: We aimed to find affected biological
processes and their regulators in both type, MSS and MSI-H, of CRC; as well as reveal specific ones in each type.
We applied meta- and network analysis on freely available transcriptome data in MSS and MSI-H colorectal cancer
from gene expression omnibus (GEO) database to detect common differentially expressed genes (DEGs) and critical
biological processes and predict their most significant regulators. Results: Our results demonstrate considerable up
and downregulation in cell cycle and lipid catabolism processes, respectively; and introduced MYC and FOXM1
as two central and up-stream regulators of DEGs in both type of CRC. Chemokine-mediated processes displayed
up-regulation in MSI-H type, while metastasis-related processes showed more activation in MSS CRC. Additionally,
DACH1 and TP53 were detected as two important transcription factors that differentially expressed just in MSS and
MSI-H, respectively. Conclusion: Our results can explain why MSI and MSS CRC display different immunotherapy
response, prognosis, and metastasis feature. Moreover, our predicted up-stream regulators in the regulatory networks
may be promising therapeutic targets.

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